title: Bit-1 mediates integrin-dependent cell survival through activation of the NFkappaB pathway.
abstract: Loss of properly regulated cell death and cell survival pathways can contribute to the development of cancer and cancer metastasis. Cell survival signals are modulated by many different receptors, including integrins. Bit-1 is an effector of anoikis (cell death due to loss of attachment) in suspended cells. The anoikis function of Bit-1 can be counteracted by integrin-mediated cell attachment. Here, we explored integrin regulation of Bit-1 in adherent cells. We show that knockdown of endogenous Bit-1 in adherent cells decreased cell survival and re-expression of Bit-1 abrogated this effect. Furthermore, reduction of Bit-1 promoted both staurosporine and serum-deprivation induced apoptosis. Indeed knockdown of Bit-1 in these cells led to increased apoptosis as determined by caspase-3 activation and positive TUNEL staining. Bit-1 expression protected cells from apoptosis by increasing phospho-IκB levels and subsequently bcl-2 gene transcription. Protection from apoptosis under serum-free conditions correlated with bcl-2 transcription and Bcl-2 protein expression. Finally, Bit-1-mediated regulation of bcl-2 was dependent on focal adhesion kinase, PI3K, and AKT. Thus, we have elucidated an integrin-controlled pathway in which Bit-1 is, in part, responsible for the survival effects of cell-ECM interactions.
authors.affiliation: The Center for Cardiovascular Research and Cell and Molecular Biology, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA.
authors.forename: Genevieve S
authors.initials: GS
authors.lastname: Griffiths
authors.forename: Melanie
authors.initials: M
authors.lastname: Grundl
authors.forename: Anna
authors.initials: A
authors.lastname: Leychenko
authors.forename: Silke
authors.initials: S
authors.lastname: Reiter
authors.forename: Shirley S
authors.initials: SS
authors.lastname: Young-Robbins
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Sulzmaier
authors.forename: Maisel J
authors.initials: MJ
authors.lastname: Caliva
authors.forename: Joe W
authors.initials: JW
authors.lastname: Ramos
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Matter
mesh_terms: D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005353:Fibronectins / Q000737:chemistry; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010957:Plasmids / Q000378:metabolism; D014162:Transfection
chemical_list: D016895:Culture Media, Serum-Free; D005353:Fibronectins; D016023:Integrins; D024101:Mitochondrial Proteins; D049452:Green Fluorescent Proteins; D002265:Carboxylic Ester Hydrolases; C483418:PTH2 protein, human; C527112:Ptrh2 protein, mouse; D053148:Caspase 3